What do medicinal chemists actually make? A 50-year retrospective

Journal of Medicinal Chemistry

Volumn 54, Issue 19, 2011, Pages 6405-6416

  Walters, W Patrick ^a   Green, Jeremy ^a   Weiss, Jonathan R ^a   Murcko, Mark A ^a  

^a VERTEX PHARMACEUTICALS   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHEMICAL STRUCTURE; CHEMISTRY; DRUG FORMULATION; DRUG STRUCTURE; DRUG SYNTHESIS; FRACTIONATION; HIGH THROUGHPUT SCREENING; HYDROGEN BOND; LIPOPHILICITY; MEDICINAL CHEMISTRY; MOLECULAR BIOLOGY; MOLECULAR WEIGHT; RETROSPECTIVE STUDY; REVIEW; SURFACE PROPERTY;

BIBLIOMETRICS; CHEMISTRY, PHARMACEUTICAL; DATABASES, FACTUAL; DRUG DESIGN; DRUG DISCOVERY; MOLECULAR STRUCTURE; PERIODICALS AS TOPIC; PHARMACEUTICAL PREPARATIONS;

EID: 80053928594     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm200504p     Document Type: Review

References (93)

1. Almog, D. M. Drug industry in "depression" Med. Sci. Monit. 2005, 11, SR1-SR4
2. Booth, B.; Zemmel, R. Prospects for productivity Nat. Rev. Drug Discovery 2004, 3, 451-456 (Pubitemid 38618127)
3. Sams-Dodd, F. Target-based drug discovery: Is something wrong? Drug Discovery Today 2005, 10, 139-147 (Pubitemid 40247812)
4. Schneider, C. K.; Schaffner-Dallmann, G. Typical pitfalls in applications for marketing authorization of biotechnological products in Europe Nat. Rev. Drug Discovery 2008, 7, 893-899
5. Wood, A. J. A proposal for radical changes in the drug-approval process N. Engl. J. Med. 2006, 355, 618-623 (Pubitemid 44200657)
6. Owens, J. Big pharma slims down to bolster productivity Nat. Rev. Drug Discovery 2007, 6, 173-174 (Pubitemid 46349928)
7. Cuatrecasas, P. Drug discovery in jeopardy J. Clin. Invest. 2006, 116, 2837-2842 (Pubitemid 44684465)
8. Carney, S. How can we avoid the productivity gap? Drug Discovery Today 2005, 10, 1011-1013 (Pubitemid 41074134)
9. Lipinski, C.; Lombardo, F.; Dominy, B.; Feeney, P. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings Adv. Drug Delivery Rev. 1997, 23, 3-25 (Pubitemid 27046991)
10. Walters, W. P.; Murcko, M. A. Prediction of "drug-likeness" Adv. Drug Delivery Rev. 2002, 54, 255-271
11. Journal of Medicinal Chemistry. http://pubs.acs.org/page/jmcmar/about. html.
12. Lajiness, M. S.; Vieth, M.; Erickson, J. Molecular properties that influence oral drug-like behavior Curr. Opin. Drug Discovery Dev. 2004, 7, 470-477 (Pubitemid 44383553)
13. dVieth, M.; Siegel, M.; Higgs, R.; Watson, I.; Robertson, D.; Savin, K.; Durst, G.; Hipskind, P. Characteristic physical properties and structural fragments of marketed oral drugs J. Med. Chem. 2004, 47, 224-232 (Pubitemid 38040506)
14. Leeson, P.; Davis, A. Time-related differences in the physical property profiles of oral drugs J. Med. Chem. 2004, 47, 6338-6348 (Pubitemid 39587257)
15. Leeson, P. D.; Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry Nat. Rev. Drug Discovery 2007, 6, 881-890 (Pubitemid 350042396)
16. Leeson, P. D.; St-Gallay, S. A.; Wenlock, M. C. Impact of ion class and time on oral drug molecular properties Med. Chem. Commun. 2011, 2, 91-105
17. Bender, A. Databases: compound bioactivities go public Nat. Chem. Biol. 2010, 6, 309
18. De Matos, P.; Alcantara, R.; Dekker, A.; Ennis, M.; Hastings, J.; Haug, K.; Spiteri, I.; Turner, S.; Steinbeck, C. Chemical entities of biological interest: an update Nucleic Acids Res. 2009, D249-D254
19. Warr, W. A. ChEMBL. An interview with John Overington, team leader, chemogenomics at the European Bioinformatics Institute Outstation of the European Molecular Biology Laboratory (EMBL-EBI) J. Comput.-Aided Drug Des. 2009, 23, 195-198
20. Ertl, P.; Rohde, B.; Selzer, P. Fast calculation of molecular polar surface area as a sum of fragment-based contributions and its application to the prediction of drug transport properties J. Med. Chem. 2000, 43, 3714-3717
21. Wang, R.; Fu, Y.; Lai, L. A new atom-additive method for calculating partition coefficients J. Chem. Inf. Comput. Sci. 1997, 37, 615-621 (Pubitemid 127603572)
22. Wang, R.; Gao, Y.; Lai, L. Calculating partition coefficient by atom-additive method Perspect. Drug Discovery Des. 2000, 19, 47-66
23. Durant, J. L.; Leland, B. A.; Henry, D. R.; Nourse, J. G. Reoptimization of MDL keys for use in drug discovery J. Chem. Inf. Comput. Sci. 2002, 42, 1273-1280 (Pubitemid 35468313)
24. Holm, S. A simple sequentially rejective multiple test procedure Scand. J. Stat. 1979, 6, 65-70
25. Proudfoot, J. R. The evolution of synthetic oral drug properties Bioorg. Med. Chem. Lett. 2005, 15, 1087-1090 (Pubitemid 40467436)
26. Lipinski, C. Drug-like properties and the causes of poor solubility and poor permeability J. Pharmacol. Toxicol. Methods 2000, 44, 235-249 (Pubitemid 32239479)
27. Gleeson, M. P. Generation of a set of simple, interpretable ADMET rules of thumb J. Med. Chem. 2008, 51, 817-834 (Pubitemid 351304691)
28. Reynolds, C. H.; Tounge, B. A.; Bembenek, S. D. Ligand binding efficiency: trends, physical basis, and implications J. Med. Chem. 2008, 51, 2432-2438 (Pubitemid 351628504)
29. Abad-Zapatero, C.; Metz, J. T. Ligand efficiency indices as guideposts for drug discovery Drug Discovery Today 2005, 10, 464-469
30. Bembenek, S. D.; Tounge, B. A.; Reynolds, C. H. Ligand efficiency and fragment-based drug discovery Drug Discovery Today 2009, 14, 278-283
31. Rees, D. C.; Congreve, M.; Murray, C. W.; Carr, R. Fragment-based lead discovery Nat. Rev. Drug Discovery 2004, 3, 660-672 (Pubitemid 39173507)
32. Hopkins, A. L.; Mason, J. S.; Overington, J. P. Can we rationally design promiscuous drugs? Curr. Opin. Struct. Biol. 2006, 16, 127-136 (Pubitemid 43221881)
33. Schuffenhauer, A.; Brown, N.; Selzer, P.; Ertl, P.; Jacoby, E. Relationships between molecular complexity, biological activity, and structural diversity J. Chem. Inf. Model. 2006, 46, 525-535
34. Posy, S. L.; Hermsmeier, M. A.; Vaccaro, W.; Ott, K. H.; Todderud, G.; Lippy, J. S.; Trainor, G. L.; Loughney, D. A.; Johnson, S. R. Trends in kinase selectivity: insights for target class-focused library screening J. Med. Chem. 2010, 54, 54-66
35. Waring, M. J. Lipophilicity in drug discovery Expert Opin. Drug Discovery 2010, 5, 235-248
36. Martin, Y. C. A practitioner's perspective of the role of quantitative structure-activity analysis in medicinal chemistry J. Med. Chem. 1981, 24, 229-237 (Pubitemid 11150485)
37. Delaney, J. S. ESOL: estimating aqueous solubility directly from molecular structure J. Chem. Inf. Comput. Sci. 2004, 44, 1000-1005
38. Mackay, D.; Bobra, A.; Shiu, W. Y.; Yalkowsky, S. H. Relationships between aqueous solubility and octanol-water partition coefficients Chemosphere 1980, 9, 701-711
39. Ran, Y.; Yalkowsky, S. H. Prediction of drug solubility by the general solubility equation (GSE) J. Chem. Inf. Comput. Sci. 2001, 41, 354-357 (Pubitemid 32408650)
40. Clark, D. E. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption J. Pharm. Sci. 1999, 88, 807-814 (Pubitemid 29398550)
41. Egan, W.; Merz, K., Jr.; Baldwin, J. Prediction of drug absorption using multivariate statistics J. Med. Chem. 2000, 43, 3867-3877
42. Aronov, A. M. Common pharmacophores for uncharged human ether-a-go-go-related gene (hERG) blockers J. Med. Chem. 2006, 49, 6917-6921 (Pubitemid 44749757)
43. Jamieson, C.; Moir, E. M.; Rankovic, Z.; Wishart, G. Medicinal chemistry of hERG optimizations: highlights and hang-ups J. Med. Chem. 2006, 49, 5029-5046 (Pubitemid 44260200)
44. Ajay; Bemis, G. W.; Murcko, M. A. Designing libraries with CNS activity J. Med. Chem. 1999, 42, 4942-4951
45. Clark, D. E. Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier penetration J. Pharm. Sci. 1999, 88, 815-821 (Pubitemid 29398551)
46. Hughes, J. D.; Blagg, J.; Price, D. A.; Bailey, S.; DeCrescenzo, G. A.; Devraj, R. V.; Ellsworth, E.; Fobian, Y. M.; Gibbs, M. E.; Gilles, R. W. Physiochemical drug properties associated with in vivo toxicological outcomes Bioorg. Med. Chem. Lett. 2008, 18, 4872-4875
47. Kelder, J.; Grootenhuis, P. D. J.; Bayada, D. M.; Delbressine, L. P. C.; Ploemen, J. P. Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs Pharm. Res. 1999, 16, 1514-1519 (Pubitemid 29510546)
48. Palm, K.; Stenberg, P.; Luthman, K.; Artursson, P. Polar molecular surface properties predict the intestinal absorption of drugs in humans Pharm. Res. 1997, 14, 568-571 (Pubitemid 27220272)
49. van de Waterbeemd, H.; Smith, D.; Beaumont, K. Property-based design: optimization of drug absorption and pharmacokinetics J. Med. Chem. 2001, 44, 1313-1333 (Pubitemid 32852106)
50. Hitchcock, S.; Pennington, L.; Lin, L.; Lanza, T., Jr. Structure-brain exposure relationships J. Med. Chem. 2006, 49, 7559-7583 (Pubitemid 46033646)
51. Veber, D.; Johnson, S.; Cheng, H.; Smith, B.; Ward, K. Molecular properties that influence the oral bioavailability of drug candidates J. Med. Chem. 2002, 45, 2615-2623 (Pubitemid 34595232)
52. Lu, J. J.; Crimin, K.; Goodwin, J. T.; Crivori, P.; Orrenius, C.; Xing, L.; Tandler, P. J.; Vidmar, T. J.; Amore, B. M.; Wilson, A. G. E.; Stouten, P. F. W.; Burton, P. S. Influence of molecular flexibility and polar surface area metrics on oral bioavailability in the rat J. Med. Chem. 2004, 47, 6104-6107 (Pubitemid 39507351)
53. Hou, T.; Wang, J.; Zhang, W.; Xu, X. ADME evaluation in drug discovery. 6. Can oral bioavailability in humans be effectively predicted by simple molecular-property based rules J. Chem. Inf. Model. 2007, 47, 460-463 (Pubitemid 46615948)
54. Blake, J. F. Examination of the computed molecular properties of compounds selected for clinical development BioTechniques 2003, Suppl.) 16-20
55. Oprea, T. I. Property distribution of drug-related chemical databases J. Comput.-Aided Mol. Des. 2000, 14, 251-264 (Pubitemid 30175944)
56. Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases J. Comb. Chem. 1999, 1, 55-68
57. Goldstein, D. M.; Gray, N. S.; Zarrinkar, P. P. High-throughput kinase profiling as a platform for drug discovery Nat. Rev. Drug Discovery 2008, 7, 391-397 (Pubitemid 351619111)
58. Pors, K.; Goldberg, F. W.; Leamon, C. P.; Rigby, A. C.; Snyder, S. A.; Falconer, R. A. The changing landscape of cancer drug discovery: a challenge to the medicinal chemist of tomorrow Drug Discovery Today 2009, 14, 1045-1050
59. Wells, J. A.; McClendon, C. L. Reaching for high-hanging fruit in drug discovery at protein-protein interfaces Nature 2007, 450, 1001-1009 (Pubitemid 350273630)
60. Schuffenhauer, A.; Brown, N.; Selzer, P.; Ertl, P. Relationships between molecular complexity, biological activity, and structural diversity J. Chem. Inf. Model. 2006, 46, 525-535
61. Yan, A.; Gasteiger, J. Prediction of aqueous solubility of organic compounds by topological descriptors QSAR Comb. Sci. 2003, 22, 821-829 (Pubitemid 38031196)
62. Lovering, F.; Bikker, J.; Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success J. Med. Chem. 2009, 52, 6752-6756
63. Ritchie, T. J.; Macdonald, S. J. F. The impact of aromatic ring count on compound developability: Are too many aromatic rings a liability in drug design? Drug Discovery Today 2009, 14, 1011-1020
64. Bemis, G. W.; Murcko, M. A. The properties of known drugs. 1. Molecular frameworks J. Med. Chem. 1996, 39, 2887-2893 (Pubitemid 26251026)
65. Bemis, G. W.; Murcko, M. A. Properties of known drugs. 2. Side chains J. Med. Chem. 1999, 42, 5095-5099 (Pubitemid 30020260)
66. Miyaura, N.; Yamada, K.; Suzuki, A. A new stereospecific cross-coupling by the palladium-catalyzed reaction of 1-alkenylboranes with 1-alkenyl or 1-alkynyl halides Tetrahedron Lett. 1979, 20, 3437-3440
67. Heck, R. F.; Nolley, J. P., Jr. Palladium-catalyzed vinylic hydrogen substitution reactions with aryl, benzyl, and styryl halides J. Org. Chem. 1972, 37, 2320-2322
68. King, A. O.; Okukado, N.; Negishi, E. Highly general stereo-, regio-, and chemo-selective synthesis of terminal and internal conjugated enynes by the Pd-catalysed reaction of alkynylzinc reagents with alkenyl halides J. Chem. Soc., Chem. Commun. 1977, 683-684
69. Chambers, J. M.; Cleveland, W. S.; Kleiner, B.; Tukey, P. A. In Graphical Methods for Data Analysis; Wadsworth & Brooks/Cole: Belmont, CA, 1983; p 62.
70. Karaman, M. W.; Herrgard, S.; Treiber, D. K.; Gallant, P.; Atteridge, C. E.; Campbell, B. T.; Chan, K. W.; Ciceri, P.; Davis, M. I.; Edeen, P. T. A quantitative analysis of kinase inhibitor selectivity Nat. Biotechnol. 2008, 26, 127-132
71. + ion channels: testing the hypotheses Biophys. J. 2008, 95, 5062-5072
72. Kenakin, T. Functional selectivity in GPCR modulator screening Comb. Chem. High Throughput Screening 2008, 11, 337-343 (Pubitemid 351830304)
73. Hawkins, M. J.; Soon-Shiong, P.; Desai, N. Protein nanoparticles as drug carriers in clinical medicine Adv. Drug Delivery Rev. 2008, 60, 876-885
74. Li, J.; Loh, X. J. Cyclodextrin-based supramolecular architectures: syntheses, structures, and applications for drug and gene delivery Adv. Drug Delivery Rev. 2008, 60, 1000-1017
75. Vintiloiu, A.; Leroux, J. C. Organogels and their use in drug delivery: a review J. Controlled Release 2008, 125, 179-192
76. Keser, G. M.; Makara, G. M. The influence of lead discovery strategies on the properties of drug candidates Nat. Rev. Drug Discovery 2009, 8, 203-212
77. Koehn, F. E.; Carter, G. T. The evolving role of natural products in drug discovery Nat. Rev. Drug Discovery 2005, 4, 206-220 (Pubitemid 40372555)
78. Li, J. W. H.; Vederas, J. C. Drug discovery and natural products: end of an era or an endless frontier? Science 2009, 325, 161-165
79. Keller, T.; Pichota, A.; Yin, Z. A practical view of " druggability" Curr. Opin. Chem. Biol. 2006, 10, 357-361
80. Wyttenbach, N.; Alsenz, J.; Grassmann, O. Miniaturized assay for solubility and residual solid screening (SORESOS) in early drug development Pharm. Res. 2007, 24, 888-898 (Pubitemid 46675389)
81. Lahoz, A.; Donato, M. T.; Castell, J. V.; Gomez-Lechon, M. J. Strategies to in vitro assessment of major human CYP enzyme activities by using liquid chromatography tandem mass spectrometry Curr. Drug Metab. 2008, 9, 12-19 (Pubitemid 351201666)
82. Hoffmann, P.; Warner, B. Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends J. Pharmacol. Toxicol. Methods 2006, 53, 87-105
83. Sambuy, Y.; De Angelis, I.; Ranaldi, G.; Scarino, M. L.; Stammati, A.; Zucco, F. The Caco-2 cell line as a model of the intestinal barrier: influence of cell and culture-related factors on Caco-2 cell functional characteristics Cell Biol. Toxicol. 2005, 21, 1-26 (Pubitemid 40767684)
84. Kansy, M.; Senner, F.; Gubernator, K. Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes J. Med. Chem. 1998, 41, 1007-1010 (Pubitemid 28207375)
85. Xu, J. J.; Henstock, P. V.; Dunn, M. C.; Smith, A. R.; Chabot, J. R.; De Graaf, D. Cellular imaging predictions of clinical drug-induced liver injury Toxicol. Sci. 2008, 105, 97-105
86. Greene, N.; Aleo, M. D.; Louise-May, S.; Price, D. A.; Will, Y. Using an in vitro cytotoxicity assay to aid in compound selection for in vivo safety studies Bioorg. Med. Chem. Lett. 2010, 20, 5308-5312
87. Kolpak, J.; Connolly, P. J.; Lobanov, V. S.; Agrafiotis, D. K. Enhanced SAR maps: expanding the data rendering capabilities of a popular medicinal chemistry tool J. Chem. Inf. Model. 2009, 49, 2221-2230
88. Ritchie, T. J.; Ertl, P.; Lewis, R. The graphical representation of ADME-related molecule properties for medicinal chemists Drug Discovery Today 2011, 16, 65-72
89. Wassermann, A. M.; Wawer, M.; Bajorath, J. Activity landscape representations for structure-activity relationship analysis J. Med. Chem. 2010, 53, 4891-4896
90. Manly, C. J.; Chandrasekhar, J.; Ochterski, J. W.; Hammer, J. D.; Warfield, B. B. Strategies and tactics for optimizing the hit-to-lead process and beyond: a computational chemistry perspective Drug Discovery Today 2008, 13, 99-109
91. Nicolaou, C. A.; Brown, N.; Pattichis, C. S. Molecular optimization using computational multi-objective methods Curr. Opin. Drug Discovery Dev. 2007, 10, 316-324 (Pubitemid 46800225)
92. Doweyko, A. M. QSAR: dead or alive? J. Comput.-Aided Mol. Des. 2008, 22, 81-89
93. Johnson, S. R. The trouble with QSAR (or how I learned to stop worrying and embrace fallacy) J. Chem. Inf. Model. 2008, 48, 25-26 (Pubitemid 351271047)